rs74667788

chrX-154349767-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001110556.2(FLNA):c.7434G>A(p.Glu2478=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,210,410 control chromosomes in the GnomAD database, including 41 homozygotes. There are 778 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., 382 hem., cov: 25)
  • Exomes 𝑓: 0.0014 (24 hom. 396 hem.)
• Consequence: FLNA NM_001110556.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.688

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-154349767-C-T is Benign according to our data. Variant chrX-154349767-C-T is described in ClinVar as [Benign]. Clinvar id is 129077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154349767-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.688 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1385/112914) while in subpopulation AFR AF= 0.043 (1340/31139). AF 95% confidence interval is 0.0411. There are 17 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.7434G>A	p.Glu2478=	synonymous_variant	46/48	ENST00000369850.10
FLNA	NM_001456.4	c.7410G>A	p.Glu2470=	synonymous_variant	45/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.7434G>A	p.Glu2478=	synonymous_variant	46/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1381 AN: 112863 Hom.: 17 Cov.: 25 AF XY: 0.0109 AC XY: 380 AN XY: 35021

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00241

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00524

GnomAD3 exomes AF: 0.00341 AC: 618 AN: 181062 Hom.: 10 AF XY: 0.00211 AC XY: 142 AN XY: 67368

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00141 AC: 1550 AN: 1097496 Hom.: 24 Cov.: 33 AF XY: 0.00109 AC XY: 396 AN XY: 363126

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.0123 AC: 1385 AN: 112914 Hom.: 17 Cov.: 25 AF XY: 0.0109 AC XY: 382 AN XY: 35082

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.00241

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00517

Alfa AF: 0.0100 Hom.: 29

Bravo AF: 0.0137

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	8.8
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74667788; hg19: chrX-153578135;